In the past 20 years, the prevalence of asthma has almost doubled, and today asthma affects 8-10% of the world's population. Asthma is a chronic inflammatory disorder of the airways and is characterized by airway hyperresponsiveness (AHR) to nonspecific stimuli and airway remodeling, which is associated with alterations in the structures and functions of the elements involved like fibroblast and myofibroblasts. Asthma is largely divided into bronchial asthma and cardiac asthma, but in general asthma means simply bronchial asthma.
One of the most representative pulmonary diseases, along with asthma, is chronic obstructive pulmonary disease (COPD) which is distinguished from asthma by accompanying obstruction of airway. COPD takes the 4 place in the causes of death world-widely and the development rate of only COPD among 10 most significant diseases is increasing. COPD is caused by pathological alterations in bronchioles and parenchyma resulted from continuous inflammation in airway and parenchyma, and so is characterized by obliterative bronchiolitis and pulmonary emphysema (the destruction of parenchyma). Chronic obstructive pulmonary diseases are exemplified by chronic obstructive bronchitis, chronic bronchiolitis and emphysema.
The treatment of asthma and such chronic obstructive pulmonary diseases has depended on using anti-inflammatory agents or bronchodilators. Glucocorticoids, leukotriene modifiers and theophyllines are the representative anti-inflammatory agents.
Although the glucocorticoid has a strong medicinal efficacy, it does not work for a specific target but for the inhibition of all immune and anti-inflammatory responses, meaning it inhibits necessary immune responses, too, and it carries serious side effects, requiring inhalation therapy. Luekotriene modifiers have fewer side effects but are limited in medicinal effects, so that they cannot regulate asthma independently and can only be used as a subsidiary. Theophylline also has problems of weak medicinal effect and side effects.
Therefore, it is required to develop an asthma treating agent with strong effect but fewer side effects. And for the development of such agents, full understanding on the developmental mechanism of asthma is prerequisite.
It is a generally accepted theory that type 1 helper T cells (Th1) or type 2 helper T cells (Th2) secret cytokines which play an important role in the development of asthma, more precisely, unbalance between cytokines, from Th1 and Th2, causes asthma (Th1/Th2 hypothesis) (Mosmann et al., J. Immunol., 136: 2348-57, 1986; Robinson et al., N. Engl. J. Med., 326: 298-304, 1992; Grunig et al., Science, 282: 2261-3, 1998; Richter et al., Am. J. Respir. Cell Mol. Biol., 25: 385-91, 2001). However, an exact mechanism of asthma induced by cytokines has not been explained, yet.
Interleukin-13 (IL-13), produced by activated Th2 lymphocytes, is a key cytokine in the pathogenesis of asthma (Grunig et al., Science, 282: 2261-3, 1998). It is supported by the findings that airway hyperresponsiveness was inhibited by suppressing the expression of IL-13 in an allergic asthma animal model but was induced again when recombinant IL-13 was administered through airway (Marsha et al., Science, 282: 2258-2261, 1998). Histological report shown in IL-13 transgenic mice was similar to that observed in asthma patients, and over-expression of IL-13 induced inflammation in airway, increase of mucus secretion and fibrosis of epithelial cells (Zhu et al., J. Clin. Invest., 103:779-788, 1999).
The idea that IL-13 can enhance AHR by promoting the infiltration of inflammatory cells, especially eosinophils, remains popular (Hargreave et al., J. Allergy clin. Immunol., 78: 825-32, 1986). However, recent evidence suggests that the induction of AHR can occur in the absence of eosinophil infiltration (Venkayya et al., Am. J. Respir. Cell Mol. Biol. 26: 202-8, 2002).
Transforming Growth Factor β1 (TGF-β1) or Vascular Endothelial Growth Factor (VEGF) is known to be involved in pathogenesis of asthma induced by IL-13 (Lee et al., Nat. Med., 10: 1095-1103, 2004).
TGF-β1, as a key element to heal the wound of tissues, induces tissue fibrosis which is a major pathological change in airway remodeling. Precisely, TGF-β1 changes fibroblasts into myofibroblasts, then myofibroblasts secret collagen more than resting fibroblasts, resulting in airway remodeling by tissue fibrosis (Vignola et al., Am. J. Respir. Crit. Care Med., 156: 591-599, 1997). This is in accordance with the finding of previous study that fibrosis in lung was induced mainly by TGF-β1 dependent pathway in IL-13 transgenic mice (Lee et al., J. Exp. Med., 194: 809-21, 2001).
During the process of tissue fibrosis, TGF-β1 induces the secretions of fibroblast growth factor-2 (FGF2 or basic Fibroblast Growth Factor, bFGF) and its receptor-1 (FGFR-1) or FGF receptor-2 (FGFR-2). FGF2 is known to be associated with the proliferation of endothelial cells or smooth muscle cells and also play an important role in angiogenesis (Nugent et al., Int. J. Biochem. Cell Biol. 32: 115-20, 2000). However, the role of FGF2 in pathogenesis of asthma and AHR has been still in question.
Vascular endothelial growth factor (VEGF) is a kind of cytokine that increases penetration of plasma protein through blood capillaries, promotes differentiation and migration of cells and induces the secretion of protease reforming a cell. VEGF is also involved in the maintenance of new blood vessels by inhibiting apoptosis, in the regulation of immune response by suppressing neuronal antigen and in the induction of cell growth and division. The present inventors demonstrated that there is a positive feedback loop between IL-13 and VEGF in relation to immune response against antigens and foreign materials (Lee et al., Nat. Med., 10: 1095-1103, 2004). Though, a role of FGF2 in pathogenesis of VEGF mediated asthma has not been elucidated.
Interferon-γ(IFN-γ) is another key cytokine secreted by Th1, in relation to the pathogenesis of asthma. Precisely, IFN-γ is a substance secreted in Th1 lymphocytes as a defender against pathogen (Fong et al., J. Imunol., 143: 2887-93, 1989), and is known to inhibit the production of Th2 cytokine (Mosann et al., J. Immunol., 136: 2348-57, 1986). Based on the Th1/Th2 hypothesis, IFN-γ has been believed to inhibit asthma, which still remains controversial. According to previous studies contradictory to the belief, airway remodeling similar to that of asthma patients is observed in IFN-γ transgenic mice (Wang et al., J. Exp. Med., 192: 1587-1600, 2000) and in particular, the severity of asthma is significantly related to the increase of IFN-γ (Corrogan et al., Lancet 1: 1129-32, 1988; Mognan et al., Am. J. Respir. Crit. Care Med., 161: 1790-6, 2000).
This contradictory idea is also supported by the founding that asthma treating agents widely used such as corticosteroids, β2-adrenergic agonists and methylxanthine derivatives, inhibit rather Th1 immune response than Th2 immune response. Thus, it is limited in explaining pathogenesis of asthma with Th1/Th2 hypothesis emphasizing the importance of promoting Th2 immune response.
In the meantime, the involvement of COPD in pathogenesis of asthma has not been elucidated, either. That is, the development and the progress of COPD has not been explained, so it is required to give full explanation on the exact mechanism of the above prior to the development of a therapeutic agent for COPD.
According to the results of recent studies with transgenic mice, IFN-γ (Wang et al., J. Exp. Med., 192: 1587-600, 2000) and IL-13 (Zheng et al., J. Clin. Invest., 106: 1081-93, 2000) proved to be involved in pathogenesis of asthma, are elements inducing pathological phenomena similar to those of human COPD. As mentioned hereinbefore, cytokines are largely secreted in immune cells, suggesting that immune response plays a key role in pathogenesis of COPD. IFN-γ and IL-13 are important factors alleviating inflammation in airway and parenchyma. For the healing of wound initiated by inflammation, the balance between attackers and defenders during the restoration of airway and pulmonary epithelial cells is particularly important (Lee et al., J. Exp. Med., 200: 377-89, 2004), which is high occupation of attackers or short of defenders might cause COPD.
The present inventors investigated the role of FGF2 in pathogenesis of IL-13, TGF-β1, VEGF and IFN-γ mediated asthma and COPD and confirmed that FGF2 suppresses AHR, induced by VEGF stimulated by IL-13 or induced by IFN-γ and inhibits pulmonary emphysema initiated by inflammation in airway and parenchyma, so that FGF2 can be effectively used for the prevention and the treatment of asthma and COPD.
And, the present inventors completed this invention by creating Th1 asthma and COPD animal models induced by ovalbumin and double stranded RNA, enabling effective and efficient experiments for the development of asthma and COPD treating agents.